The worldwide incidence of diabetes has increased from an estimated 30,000,000 patients in 1985 to an estimated 245,000,000 patients in 2007, and will further increase to 380,000,000 by 2025 (Source: International Diabetes Federation). The treatment cost of diabetes and diabetic complications is reaching $232,000,000,000 in 2007 and may be expected to be over $302,500,000,000 by 2025. Chronic diabetes gives rise to several diabetic complications such as diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic cataract, diabetic cystopathy, diabetic corneal keratopathy, diabetic dermopathy, diabetic microangiopathy, myocardial infarction, macular edema, impaired neural conduction and diabetic wounds.
Treatment of diabetic complications is independent of blood glucose level control. Thus, standard anti-diabetic drugs are not suitable as treatment options for diabetic complications. There is an immediate requirement for new compositions and treatments for diabetic complications.
One of the major underlying problem facing diabetics is impaired wound healing. Fifteen percent of all people with diabetes (2.6 million) are expected to develop foot ulcers during their lifetime. These ulcers tend to be chronic in nature, as they do not heal or heal extremely slowly. Currently, there are approximately 750,000 patients with diabetic foot ulcers in the United States, 980,000 in Europe and 1.1 million in the rest of the world, totaling 2.8 million patients. Diabetic foot ulcers are a serious problem, as up to 25% of diabetic foot ulcers will eventually require amputation. The medical importance of diabetic wound healing cannot be overstated. The capacity to heal is central to human well being, as wound healing enables a patient to overcome traumatic injury, surgery, and wounds due to metabolic disorders such as diabetes, microbial or other physical or chemical agents.
The ineffective healing of wounds is a serious problem in diabetes, contributing to increased morbidity (J. J. Reynolds, British J Dermatol, 112 715-723 (1985); J. A. Galloway and C. R. Shuman, Am J Med, 34 177-191 (1963); and S. H. Pearl and I. O. Kanat, J Foot Surg, 27, 268-270 (1988)). The reparative response in wound healing is orchestrated by multiple cellular elements which work together in many ways, including infiltration of the lesion by inflammatory effector cells. Subsequent to this, fibroblastic elements together with inflammatory effector cells provide antibacterial mechanisms and promote removal of necrotic tissue, as well as the laying down of new connective tissue. A fundamental disorder of glucose metabolism may disturb these complex and interactive protective processes.
Previous work has suggested that cellular dysfunction in diabetic wound healing involves defective neutrophil function (J. D. Bagdade et al., Diabetes, 27, 677-681 (1978); C. M. Nolan et al., Diabetes, 27, 889-894 (1978); A. G. Mowat and J. Baum, J. Clin Invest December, 50, 2541-2549 (1971)), delayed infiltration of the wound with inflammatory cells (D. G. Greenhalgh et al., Am J Pathol, 136, 1235 (1990) and Fahey et al., Surg 214, 175-180 (1991)), decreased production of collagen (W. H. Goodson and T. K. Hunt, J Anal, 124, 401-411 (1977) and W. H. Goodson and T. K. Hunt, Diabetes April, 35, 491-495 (1986)), and diminished activity of endogenous growth factors, such as basic fibroblast growth factor, which could provide a basis for the slower formation of granulation tissue and wound closure.
Over 100 known physiologic factors contribute to wound healing deficiencies in individuals with diabetes (Oyama, et al. Diabetes: Research and Clinical Practice 73, 227-234 (2006); H. Brem and M. Tomic-Canic, J. Clin. Invest., 117, 1219-1222 (2007)). These factors include decreased or impaired growth factor production, angiogenic response, macrophage function, collagen accumulation, epidermal barrier function, quantity of granulation tissue, keratinocyte and fibroblast migration and proliferation, number of epidermal nerves, bone healing, and balance between the accumulation of extracellular matrix (ECM) components and their remodeling by metalloproteinases (MMPs). Wound healing occurs as a cellular response to injury and involves activation of keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets. Many growth factors and cytokines released by these cell types are needed to coordinate and maintain healing. Molecular analyses of biopsies from the epidermis of patients have identified pathogenic markers that correlate with delayed wound healing. These include the over expression of c-myc and nuclear localization of β-catenin. Coupled with a reduction in and abnormal localization of epidermal growth factor receptor (EGFR) and activation of the glucocorticoid pathway, keratinocyte migration is inhibited. At the non healing edge (callus) of diabetic foot ulcers (DFUs), keratinocytes show an absence of migration, hyper proliferation, and incomplete differentiation. Fibroblasts demonstrate a phenotypic change as well as decreased migration and proliferation.
The diabetic foot ulcer etiology is complex, and wound healing is often not very successful for a variety of reasons. The diabetic foot ulcer's etiology is associated with peripheral vascular disease, autonomic neuropathy and endothelial dysfunction. Metabolic conditions that are not optimal for wound-healing delay the process even more (hyperglycemia, hyperlipidemia, hyperinsulinemia, pro-coagulative state) and may also be present. Wound healing is a complex process characterized by three overlapping phases: inflammation, tissue formation and tissue remodeling (H. Brem and M. Tomic-Canic, J. Clin. Invest., 117, 1219-1222 (2007)). This sequential process emanates by the interaction of cells in the dermis and epidermis, in parallel with the release of chemical mediators from inflammatory cells, fibroblasts and keratinocytes. During tissue formation, growth factors synthesized by local and migratory cells stimulate fibroblasts to migrate into the wound where they proliferate and construct an extracellular matrix. Diabetes is known to be associated with a variety of alterations in connective tissue metabolism, as a result of which diabetics face the problem of poor wound healing. The common features observed during diabetic wound healing in rats are inflammation, slow beginning of the initial healing phase which tends to prolong healing time, lower density of neutrophils in healing areas and failure in the replacement of neutrophils by macrophages in the areas where healing occurs. Cutaneous wound healing is a complex and well orchestrated biological process requiring the coordinated migration and proliferation of both keratinocytes and fibroblasts, as well as other cell types. Wounding the epidermis generates cytokines, growth factors, proteases and initiates the synthesis of extracellular matrix components, all of which can regulate the processes of keratinocyte migration and proliferation essential for re-epithelialization.
Loss of collagen related to diabetes may be due to decreased levels of synthesis or enhanced metabolism of newly synthesized collagen or both. These qualitative and quantitative abnormalities contribute to the impaired wound healing observed in diabetic condition.
Various mechanisms of cell injuries in diabetes mellitus have been reported (Sakata et al., J. Atheroscler. Thromb. 3,169-176 (2000); D. K. Ways, M. J. Sheetz, Vitam. Horm. 60, 149-193 (2000); Mashima, et al., Curr. Opin. Lipidol. 4, 411-418 (2001)), including accelerated glycation, increased protein kinase C activity and increased oxidative stress, but the precise mechanism is not fully understood. Hotta's group (N. Sakamoto, J. H. Kinoshita, P. F. Kador, N. Hotta, Polyol Pathway and its Role in Diabetic Complications, Elsevier Science B.V., Amsterdam, 1988) proposed the involvement of the polyol pathway as a mechanism of various organ injuries induced by high concentration of glucose. The polyol pathway consists of two steps. The first is the conversion of glucose to sorbitol, and the second is the conversion of sorbitol to fructose. The key enzyme is aldose reductase that converts glucose to sorbitol. This enzyme is found in many tissues. Hyperglycemia enhances the polyol pathway, resulting in accumulation of sorbitol in the cells. Accumulation of sorbitol in cells causes various organ injuries. High osmotic pressure and high oxidative stress have been proposed as the mechanisms by which the polyol pathway is involved in cell injury. However, the precise mechanism of the polyol pathway is not yet fully understood. It has been observed that high glucose-induced endothelial cell damages may be mediated by activation of the polyol pathway accompanied by augmented oxidative stress. The use of aldose reductase inhibitors suggest that inhibition of the polyol pathway may prevent endothelial cell damages in diabetic conditions.
The beta adrenergic receptor is known to be involved in the process of wound healing, and agonists have shown to delay the wound healing process. It has also been demonstrated that beta-adrenergic receptor-induction inhibits keratinocyte migration, which delays wound healing (Chen et al., J. Invest. Dermatol. 119, 1261-8 (2002)). There are other references for topical applications in the form of aqueous solutions or opthalmic drops of beta-antagonists (Reidy et al., Br. J. Ophthalmol. 78, 377-380 (1994). Denda et al., J. Invest. Dermatol. 121, 142-148 (2003)). Furthermore, the fact that beta blockers are able to increase angiogenesis in infarcted hearts implies that they promote angiogenesis, which may be useful in wound healing (Am J Physiol Heart Circ Physiol. 2005). In addition, propranolol is shown to enhance pulmonary collagen by controlling the ratio of cAMP and cGMP (R C Lindenschmidt and H P Witschi; Pharmacology and Experimental Therapeutics, 232, 346-350 (1985)). However, beta adrenergic receptor blockers have not been reported for their use in diabetic complications like diabetic wound healing, and diabetes wound healing involves a different etiology from regular or traumatic wound healing.